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Myelination in the brain may be key to ‘learning’ opioid addiction



Myelination in the brain may be key to ‘learning’ opioid addiction

Our brains, even in adulthood, continually adapt to what we do, strengthening or weakening neural pathways as we practice new skills or abandon old habits. Now, research by Stanford Medicine scientists has found that a particular type of neuroplasticity, known as adaptive myelination, can also contribute to drug addiction.

In adaptive myelination, more active brain circuits gain more myelin — the fatty insulation that allows electrical signals to travel faster and more efficiently through nerve fibers. Learning to juggle or practicing the piano, for example, gradually increases myelination in the brain circuits involved, optimizing for these abilities.

But the same adaptive myelination that is essential to learning, attention and memory has a dark side. In the new study in mice, researchers found that a single dose of morphine was enough to trigger the steps leading to myelination of dopamine-producing neurons — part of the brain’s reward circuitry — spurring the mice to seek out more of the drug. When myelination was blocked, the mice made no effort to find more morphine.

The new findings, to be published June 5 in Nature, show how using addictive drugs can drive maladaptive myelination of the brain’s reward circuitry, which in turn reinforces drug-seeking behavior.

Myelin matters

“Myelin development does not complete until we’re in our late 20s or early 30s, which is kind of fascinating,” said Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and senior author of the study.

Even after such a protracted developmental period, special cells in the brain called oligodendrocytes continue to generate new myelin in some brain regions.

“What we’ve come to understand over the last decade or so is that myelin, in some parts of the nervous system, is actually plastic and adaptable to experience,” Monje said. “The activity of a neuron can regulate the extent to which its axon is myelinated.”

Research in neuroplasticity has mostly focused on changes that occur at synapses — where neurons meet and communicate with each other. Adaptive myelination adds a new layer to how our brains learn from experience.

Much of the foundational knowledge about adaptive myelination has come from Monje’s lab. In 2014, her team reported that stimulating the premotor cortex of mice increased the myelination of neurons there and improved limb movement. Subsequent studies by her lab and collaborators have found that mice need adaptive myelination for spatial learning — to navigate a maze, for example, or to remember a threatening situation.

Reward learning

In the new study, Monje’s team wondered whether adaptive myelination was involved in reward learning. The researchers generated a rewarding experience in mice by giving them cocaine or morphine, or by directly stimulating their dopamine-producing neurons using optogenetic techniques.

Within three hours of a single injection of cocaine or morphine or 30 minutes of stimulation, the researchers were surprised to see a proliferation of the specialized stem cells that are destined to become myelin-producing oligodendrocytes. The proliferation was isolated to a brain region known as the ventral tegmental area, which is involved in reward learning and addiction.

“We didn’t think one dose of morphine or cocaine would do anything,” said Belgin Yalcin, PhD, lead author of the new study and an instructor in neurology and neurological sciences. “But within three hours there was a change. A very mild change, but still a change.”

Both the speed and specificity of the changes were unexpected, the researchers said.

When researchers repeated the drug injections or brain stimulation for several days, then examined the mice a month later, they indeed found more oligodendrocytes and more myelinated dopamine-producing cells, with thicker myelin around their axons, again only in the ventral tegmental area.

Even a slight thickening of myelin — in this case, by several hundred nanometers — can affect brain function and behavior.

“Details matter in terms of myelin plasticity,” Yalcin said. “So little can make such a big difference in conduction velocity and the synchronicity of the circuit.”

Potent rewards

To see how the myelination translated into behavior, the researchers placed each mouse in a box where it could move freely between two chambers. In one chamber, the mice received a daily injection of morphine. (The researchers decided to focus on morphine because of its relevance to the opioid epidemic.) After five days, the mice strongly preferred the chamber where they had received the drug and would linger there, hoping for another hit.

The morphine stimulated the mice’s reward circuitry (specifically, the dopamine-producing neurons in the ventral tegmental area), increased the myelination of these neurons and tuned their brains for further reward-seeking behavior.

Curiously, when the researchers tested a food reward instead of morphine, the mice did not develop more food-seeking behavior, perhaps because the reward was less potent, the researchers said.

“You might not want your reward circuits to be modified by everyday kinds of rewards,” Monje said.

From mice to men

“In the healthy nervous system, adaptive myelination tunes circuit dynamics in a way that supports healthy cognitive functions like learning, memory and attention,” Monje said.

But as the new study demonstrates, the process can go awry, enhancing circuits that drive unhealthy behaviors or failing to enhance circuits required for healthy brain function.

In 2022, Monje’s lab reported that adaptive myelination could explain why some epileptic seizures worsen over time. The experience of seizures drives more myelination of the circuits involved, allowing faster and more synchronized signaling, which become more frequent and severe seizures. Her team also has found that reduced myelin plasticity contributes to “chemo-fog,” the cognitive impairments that often follow cancer treatment.

In the new study, the precise biochemical steps by which a drug reward leads to myelination are not completely clear. The researchers tried bathing oligodendrocyte precursor cells in dishes of morphine or dopamine and determined that neither chemical directly causes proliferation of these cells.

“A future direction would be to understand what exactly these myelin-forming cells are responding to that comes from the activity of dopaminergic neurons,” Yalcin said.

They found that a pathway known as BDNF-TrkB signaling is part of the story. When they blocked this pathway, the mice did not generate new oligodendrocytes and did not acquire a preference for the chamber where they received the drug.

“The mice just couldn’t learn where they received their morphine reward,” Monje said.

Ultimately, a better understanding of adaptive myelination might reveal new strategies to help people recover from opioid addiction. Perhaps the process can be reversed and an addiction unlearned.

“We don’t know whether these changes are permanent, but there’s reason to believe that they would not be,” Monje said. “We think that myelin plasticity is bidirectional — you can both increase myelination of a circuit and decrease myelination of a circuit.”

The study was supported by funding from the Gatsby Charitable Foundation, the Wu Tsai Neurosciences Institute NeuroChoice Initiative, the National Institute of Neurological Disorders and Stroke (grant R01NS092597), the NIH Director’s Pioneer Award (DP1NS111132), the National Institute for Drug Abuse (P50DA042012, T32DA035165 and K99DA056573), the National Cancer Institute (P50CA165962, R01CA258384 and U19CA264504), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Cancer Grand Challenges and Cancer Research UK, a Maternal and Child Health Research Institute at Stanford University Postdoctoral Award, and a Dean’s Postdoctoral Fellowship at Stanford University.

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Ancient ocean slowdown warns of future climate chaos




Ancient ocean slowdown warns of future climate chaos

When it comes to the ocean’s response to global warming, we’re not in entirely uncharted waters. A UC Riverside study shows that episodes of extreme heat in Earth’s past caused the exchange of waters from the surface to the deep ocean to decline.

This system has been described as the “global conveyer belt,” because it redistributes heat around the globe through the movement of the ocean waters, making large portions of the planet habitable.

Using tiny, fossilized shells recovered from ancient deep-sea sediments, the study in the Proceedings of the National Academy of Sciences demonstrates how the conveyor belt responded around 50 million years ago. At that time, Earth’s climate resembled conditions predicted by the end of this century, if significant action is not taken to reduce carbon emissions.

Oceans play a crucial role in regulating Earth’s climate. They move warm water from the equator toward the north and south poles, balancing the planet’s temperatures. Without this circulation system, the tropics would be much hotter and the poles much colder. Changes in this system are linked to significant and abrupt climate change.

Furthermore, the oceans serve a critical role in removing anthropogenic carbon dioxide from the atmosphere. “The oceans are by far the largest standing pool of carbon on Earth’s surface today,” said Sandra Kirtland Turner, vice-chair of UCR’s Department of Earth and Planetary Sciences and first author of the study.

“Today, the oceans contain nearly 40,000 billion tons of carbon — more than 40 times the amount of carbon in the atmosphere. Oceans also take up about a quarter of anthropogenic CO2 emissions,” Kirtland Turner said. “If ocean circulation slows, absorption of carbon into the ocean may also slow, amplifying the amount of CO2 that stays in the atmosphere.”

Previous studies have measured changes in ocean circulation in Earth’s more recent geologic past, such as coming out of the last ice age; however, those do not approximate the levels of atmospheric CO2 or warming happening to the planet today. Other studies provide the first evidence that deep ocean circulation, particularly in the North Atlantic, is already starting to slow.

To better predict how ocean circulation responds to greenhouse gas-driven global warming, the research team looked to the early Eocene epoch, between roughly 49 and 53 million years ago. Earth then was much warmer than today, and that high-heat baseline was punctuated by spikes in CO2 and temperature called hyperthermals.

During that period, the deep ocean was up to 12 degrees Celsius warmer than it is today. During the hyperthermals, the oceans warmed an additional 3 degrees Celsius.

“Though the exact cause of the hyperthermal events is debated, and they occurred long before the existence of humans, these hyperthermals are the best analogs we have for future climate change,” Kirtland Turner said.

By analyzing tiny fossil shells from different sea floor locations around the globe, the researchers reconstructed patterns of deep ocean circulation during these hyperthermal events. The shells are from microorganisms called foraminifera, which can be found living throughout the world’s oceans, both on the surface and on the sea floor. They are about the size of a period at the end of a sentence.

“As the creatures are building their shells, they incorporate elements from the oceans, and we can measure the differences in the chemistry of these shells to broadly reconstruct information about ancient ocean temperatures and circulation patterns,” Kirtland Turner said.

The shells themselves are made of calcium carbonate. Oxygen isotopes in the calcium carbonate are indicators of temperatures in the water the organisms grew in, and the amount of ice on the planet at the time.

The researchers also examined carbon isotopes in the shells, which reflect the age of the water where the shells were collected, or how long water has been isolated from the ocean surface. In this way, they can reconstruct patterns of deep ocean water movement.

Foraminifera can’t photosynthesize, but their shells indicate the impact of photosynthesis of other organisms nearby, like phytoplankton. “Photosynthesis occurs in the surface ocean only, so water that has recently been at the surface has a carbon-13 rich signal that is reflected in the shells when that water sinks to the deep ocean,” Kirtland Turner said.

“Conversely, water that has been isolated from the surface for a long time has built up relatively more carbon-12 as the remains of photosynthetic organisms sink and decay. So, older water has relatively more carbon-12 compared to ‘young’ water.”

Scientists often make predictions about ocean circulation today using computer climate models. They use these models to answer the question: ‘how is the ocean going to change as the planet keeps warming?’ This team similarly used models to simulate the ancient ocean’s response to warming. They then used the foraminifera shell analysis to help test results from their climate models.

During the Eocene, there were about 1,000 parts per million (ppm) of carbon dioxide in the atmosphere, which contributed to that era’s high temperatures. Today, the atmosphere holds about 425 ppm.

However, humans emit nearly 37 billion tons of CO2 into the atmosphere each year; if these emission levels continue, similar conditions to the Early Eocene could occur by the end of this century.

Therefore, Kirtland Turner argues it is imperative to make every effort to reduce emissions.

“It’s not an all-or-nothing situation,” she said. “Every incremental bit of change is important when it comes to carbon emissions. Even small reductions of CO2 correlate to less impacts, less loss of life, and less change to the natural world.”

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Pacific coast gray whales have gotten 13% shorter in the past 20-30 years, Oregon State study finds




Pacific coast gray whales have gotten 13% shorter in the past 20-30 years, Oregon State study finds

Gray whales that spend their summers feeding in the shallow waters off the Pacific Northwest coast have undergone a significant decline in body length since around the year 2000, a new Oregon State University study found.

The smaller size could have major consequences for the health and reproductive success of the affected whales, and also raises alarm bells about the state of the food web in which they coexist, researchers say.

“This could be an early warning sign that the abundance of this population is starting to decline, or is not healthy,” said K.C. Bierlich, co-author on the study and an assistant professor at OSU’s Marine Mammal Institute in Newport. “And whales are considered ecosystem sentinels, so if the whale population isn’t doing well, that might say a lot about the environment itself.”

The study, published in Global Change Biology, looked at the Pacific Coast Feeding Group (PCFG), a small subset of about 200 gray whales within the larger Eastern North Pacific (ENP) population of around 14,500. This subgroup stays closer to shore along the Oregon coast, feeding in shallower, warmer waters than the Arctic seas where the bulk of the gray whale population spends most of the year.

Recent studies from OSU have shown that whales in this subgroup are smaller and in overall worse body condition than their ENP counterparts. The current study reveals that they’ve been getting smaller in recent decades.

The Marine Mammal Institute’s Geospatial Ecology of Marine Megafauna (GEMM) Lab has been studying this subgroup of gray whales since 2016, including flying drones over the whales to measure their size. Using images from 2016-2022 of 130 individual whales with known or estimated age, researchers determined that a full-grown gray whale born in 2020 is expected to reach an adult body length that is 1.65 meters (about 5 feet, 5 inches) shorter than a gray whale born prior to 2000. For PCFG gray whales that grow to be 38-41 feet long at full maturity, that accounts for a loss of more than 13% of their total length.

If the same trend were to happen in humans, that would be like the height of the average American woman shrinking from 5 feet, 4 inches to 4 feet, 8 inches tall over the course of 20 years.

“In general, size is critical for animals,” said Enrico Pirotta, lead author on the study and a researcher at the University of St. Andrews in Scotland. “It affects their behavior, their physiology, their life history, and it has cascading effects for the animals and for the community they’re a part of.”

Whale calves that are smaller at weaning age may be unable to cope with the uncertainty that comes with being newly independent, which can affect survival rates, Pirotta said.

For adult gray whales, one of the biggest concerns is reproductive success.

“With them being smaller, there are questions of how effectively these PCFG gray whales can store and allocate energy toward growing and maintaining their health. Importantly, are they able to put enough energy toward reproduction and keep the population growing?” Bierlich said.

Scarring on PCFG whales from boat strikes and fishing gear entanglement also makes the team concerned that smaller body size with lower energy reserves may make the whales less resilient to injuries.

The study also examined the patterns of the ocean environment that likely regulate food availability for these gray whales off the Pacific coast by tracking cycles of “upwelling” and “relaxation” in the ocean. Upwelling sweeps nutrients from deeper to shallower regions, while relaxation periods then allow those nutrients to remain in shallower areas where light allows for growth of plankton and other tiny organisms, including the prey of gray whales.

“Without a balance between upwelling and relaxation, the ecosystem may not be able to produce enough prey to support the large size of these gray whales,” said co-author Leigh Torres, associate professor and director of the GEMM Lab at OSU.

The data show that whale size declined concurrently with changes in the balance between upwelling and relaxation, Pirotta said.

“We haven’t looked specifically at how climate change is affecting these patterns, but in general we know that climate change is affecting the oceanography of the Northeast Pacific through changes in wind patterns and water temperature,” he said. “And these factors and others affect the dynamics of upwelling and relaxation in the area.”

Now that they know the PCFG gray whales’ body size is declining, researchers say they have a lot of new questions about downstream consequences of that decline and the factors that could be contributing to it.

“We’re heading into our ninth field season studying this PCFG subgroup,” Bierlich said. “This is a powerful dataset that allows us to detect changes in body condition each year, so now we’re examining the environmental drivers of those changes.”

The other co-authors on the paper were Lisa Hildebrand, Clara Bird and Alejandro Ajó at OSU and Leslie New at Ursinus College in Pennsylvania.

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Western agricultural communities need water conservation strategies to adapt to future shortages




Western agricultural communities need water conservation strategies to adapt to future shortages

The Western U.S. is heavily reliant on mountain snowpacks and their gradual melt for water storage and supply, and climate change is expected to upend the reliability of this natural process. Many agricultural communities in this part of the country are examining ways to adapt to a future with less water, and new research shows that a focus on supplementing water supply by expanding reservoir capacity won’t be enough to avert future water crises.

Led by scientists at the Desert Research Institute (DRI), the study published June 11 in Earth’s Future. By identifying agricultural communities considered at-risk from looming changes in snowfall and snowmelt patterns, the researchers found that water conservation measures like changes in crop type and extent were more stable adaptive strategies than changes to reservoir capacity. By the end of the century, many areas could have less than half the water they have historically relied on to refill their reservoirs, but changing the types and extent of their crops could help by restoring an average of about 20% of reservoir capacity.

The research team included scientists with the diversity of expertise needed to capture the complexities of water systems while balancing concerns for locally focused adaptation. Beatrice Gordon, lead author of the study and sociohydrologist and postdoctoral researcher at DRI, says the research is needed to inform water management at the local level, where most decisions are made. Gordon herself grew up on a ranch in Wyoming, where she learned firsthand the challenges that face water-insecure communities — an experience that helped lead to her research focus on agriculture and water in the Western U.S.

“A lot of decisions about water are made at the local level, but there’s this big disconnect between that reality and the macro-scale level of most research on this topic,” Gordon says. “We really wanted to understand what the future could look like at the scale that most communities manage their water resources. What are the levers that folks in these communities have when it comes to a future with less snow?”

Mountain snowpacks have historically acted as nature’s water towers across much of the region by storing winter precipitation and releasing it downstream during drier months. Water management systems were designed with this process in mind, but climate change is altering snowmelt patterns in ways that will make it difficult for existing systems to meet the needs of downstream water users. As the world’s largest user of freshwater, irrigated agriculture is at particularly high risk from these changes.

Strategies for addressing water shortages that focus on augmenting supply include expanding reservoirs and replenishing groundwater with surplus water, but these approaches become less effective as the timing and availability of precipitation become more unpredictable. In contrast, water conservation strategies such as reducing total crop acreage, periodic crop fallowing, and shifting toward higher value crops can help manage these risks.

To find out how risk management practices could work on a community-level scale, the researchers built a comprehensive risk assessment framework based on guidance from the Intergovernmental Panel on Climate Change (IPCC). For each of 13 communities, they gathered historical data on irrigation water supply, agricultural water demand, snow storage and snowmelt patterns, and more. They then used projections for the future climate through 2100 to understand how supply and demand dynamics may change in the near future.

“We gathered all these data together and looked at the picture of risk, and then also the ways that adaptation could reduce risk,” Gordon says. “Our goal was really to make this as relevant as possible for the people who are actually making decisions on the ground.”

“Dr. Gordon assembled a very impressive and unprecedented dataset for this paper linking agricultural water supply and demand across the Western United States,” says study co-author Gabrielle Boisramé, assistant research professor at DRI.

The Western agricultural communities the researchers selected are located in headwaters areas, making them both subject to significant changes in future climate and sentinels for the future of the West. Several of them are located in the Upper Colorado River Basin, which feeds into the main stem of the river — a water system that supports more than 40 million people.

“A lot of these areas are providing downstream water to other communities,” Gordon says. “So, if they have an increase in demand and a decrease in supply, it impacts not only that area, but also the areas that rely on that water downstream.”

The study results show that there will be a stark decline in how much many of these communities will be able to refill their reservoirs in just a few decades, with some seeing declines to about half of the water they were historically able to store. A drop that significant is particularly acute in many of the smaller reservoirs that can only hold about a year’s worth of water.

“It shows how important it is to dedicate effort — now, not in 20 to 50 years — to figuring out how we, as scientists, can provide better information about water conservation,” Gordon says. “And I think that there’s an opportunity to really think about how we support communities in these efforts, especially small communities in headwaters regions that might be fully dependent on agriculture.”

“Our results indicate the importance of water conservation as an adaptive strategy in a warmer future with less snow,” she continues. “And that’s broadly true across a lot of different places in the Western U.S.”

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